The role of cellular senescence in bone loss and recovery in periodontal disease

细胞衰老在牙周病骨质流失和恢复中的作用

• 批准号: 10741898
• 负责人: Mizuho Kittaka
• 金额: $ 15.85万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741898
• 关键词: Address; Adult; Adverse effects; Age; Age-Related Bone Loss; Aging; Alveolar Bone Loss; Attenuated; Biological; Biological Assay; Biology; Bone Resorption; Cell Aging; Cells; Clinical Trials; Development; Disease; Disease model; Excision; Foundations; Future; Genes; Gingiva; Goals; Human; Immunohistochemistry; Induction of Apoptosis; Inflammation; Life; Ligature; Mandible; Mature Bone; Measurement; Mechanics; Mediator; Mus; Musculoskeletal; Osteoclasts; Osteogenesis; Outcome; Outcome Study; Pathologic; Pathology; Patients; Periodontal Diseases; Periodontal Ligament; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Prevalence; Prevention strategy; Public Health; Recovery; Role; Testing; Therapeutic Intervention; Tissues; Tooth Cervix; Tooth Loss; Tooth structure; Work; age related; alternative treatment; alveolar bone; bone; bone loss; clinical efficacy; conventional therapy; experimental study; fisetin; improved; novel therapeutics; phenotypic biomarker; prevent; senescence; stressor; telomere; therapeutically effective; treatment strategy

Project Summary/Abstract The prevalence of tooth-supporting alveolar bone loss by periodontal disease (PD) steeply rises in the 3rd and 4th decades of life. As such, PD is a leading cause of tooth loss in adults. Mechanisms behind the increased susceptibility to PD bone loss in adulthood are unknown. 17 to 23% of PD patients do not respond to current treatment and thus progress to tooth loss. Our long-term goal is to identify the mechanism of age-related bone loss in PD to develop mechanistically based therapies of PD bone loss. A potential factor in the development of PD bone loss is the accumulation of senescent cells. Senescent cell accumulation in tissues is increasingly recognized as a driver of age-associated disorders. To mitigate the deleterious effects, senescent cells can be removed by drugs called senolytics that selectively induce apoptosis in senescent cells. Fisetin is a recently characterized senolytic without observable adverse effects and is being evaluated in clinical trials targeting pathological conditions hallmarked by senescent cell burden. Our preliminary studies using the ligature-induced PD (LIP) model showed that LIP induces initial rapid bone resorption followed by a rapid recovery due to bone formation by day 14 in young mice (2.5 months). In contrast, significant bone loss remained at day 14 in mature mice (8-12 months). Also, mature mice showed greater bone volume loss compared to young mice, indicating the increased susceptibility to LIP-induced bone loss in mature mice. Furthermore, bone formation rate in mature mice with LIP was lower than young mice, suggesting that diminished bone formation rate is responsible for the increased susceptibility to LIP-induced bone loss in mature mice. We found increases in expression levels of senescence marker genes in periodontal tissue of mature mice before PD induction, suggesting that accumulation of senescent cells in the tissue increase the susceptibility to LIP-induced bone loss in mature mice. Our hypothesis is that accumulation of the senescent cells is a critical factor responsible for inhibiting bone recovery and for increasing bone loss susceptibility in the pathology of PD bone loss, and that senolytic treatment will improves the PD-driven bone loss. Here, we propose the following aims: Specific Aim 1: Determine if the clearance of pre-existing senescent cells by the senolytic, fisetin, will prevent PD alveolar bone loss. 12-month-old mice will be pre- treated with fisetin to clear and prevent age-related senescent accumulation before inducing LIP, and we will analyze the effect of senescent cell clearance by fisetin pre-treatment on LIP-induced bone loss. Specific Aim 2: Determine if fisetin treatment will induce recovery from PD-induced bone loss. We will induce LIP in 12- months-old mice and wait until bone resorption progress to detectable levels before starting fisetin treatment. We will then analyze bone loss induced by LIP. Our team is uniquely suited to conduct these experiments with expertise in periodontology, bone biology, and cellular senescence in musculoskeletal tissue. Outcomes from this work will lead us to further mechanistic studies of the role of senescence in PD toward our long-term goal.

项目概要/摘要 牙周病（PD）导致牙齿支持牙槽骨丧失的患病率在第三个世纪急剧上升 和人生的第四个十年。因此，PD 是成人牙齿脱落的主要原因。增长背后的机制 成年期对 PD 骨丢失的易感性尚不清楚。 17% 至 23% 的 PD 患者对当前的治疗没有反应 治疗，从而导致牙齿脱落。我们的长期目标是确定与年龄相关的骨骼的机制 开发基于机制的 PD 骨丢失疗法。发展的潜在因素 PD骨质流失的主要原因是衰老细胞的积累。衰老细胞在组织中的积累越来越多 被认为是与年龄相关的疾病的驱动因素。为了减轻有害影响，可以将衰老细胞 被称为 senolytics 的药物去除，选择性诱导衰老细胞凋亡。非瑟酮是最近 senolytic 的特点是没有可观察到的副作用，并且正在针对目标的临床试验中进行评估 以衰老细胞负担为特征的病理状况。 我们使用结扎诱导 PD (LIP) 模型进行的初步研究表明，LIP 诱导初始快速 年轻小鼠（2.5 个月）的骨吸收随后因骨形成而迅速恢复，并在第 14 天时出现。在 相比之下，成熟小鼠（8-12 个月）在第 14 天仍存在明显的骨质流失。此外，成熟小鼠还表现出 与年轻小鼠相比，骨量损失更大，表明对 LIP 诱导的骨的敏感性增加 成熟小鼠的损失。此外，患有 LIP 的成熟小鼠的骨形成率低于年轻小鼠， 表明骨形成率降低是 LIP 诱导的易感性增加的原因 成熟小鼠的骨质流失。我们发现牙周衰老标志基因的表达水平增加 PD诱导前成熟小鼠的组织，表明组织中衰老细胞的积累 增加成熟小鼠对 LIP 诱导的骨质流失的敏感性。我们的假设是，积累 衰老细胞是抑制骨质恢复和增加骨质流失的关键因素 PD 骨质流失病理学的易感性，并且 senolytic 治疗将改善 PD 驱动的骨质流失 损失。在此，我们提出以下目标： 具体目标 1：确定是否清除现有的 衰老细胞中的senolytic、fisetin，将防止PD牙槽骨丢失。 12个月大的小鼠将被预先 在诱导 LIP 之前用非瑟酮处理以清除和预防与年龄相关的衰老积累，我们将 分析非瑟酮预处理清除衰老细胞对 LIP 诱导的骨丢失的影响。具体目标 2：确定非瑟酮治疗是否会促使 PD 引起的骨质流失恢复。我们将在 12 年内诱导 LIP 几个月大的小鼠，等到骨吸收进展到可检测的水平，然后开始非瑟酮治疗。 然后我们将分析 LIP 引起的骨质流失。我们的团队非常适合进行这些实验 牙周病学、骨生物学和肌肉骨骼组织细胞衰老方面的专业知识。结果来自 这项工作将引导我们进一步研究衰老在帕金森病中的作用，以实现我们的长期目标。